Investigating the Role of a Lifestyle Intervention on Novel Estrogen Biomarkers ABSTRACT Background: There is a large accumulation of evidence implicating estrogen in breast and endometrial cancer development. Estrogen metabolites within the catechol estrogen (CE) pathway, in particular hydroxy estrogen (HE) quinones, are capable of forming DNA adducts which may lead in certain instances to DNA mutations. Thus, the biological plausibility of the involvement of the HE quinones in the initiation of carcinogenesis coupled with the fact that CE metabolism is reversible indicates that this pathway is ideal for targeting in an intervention study. In addition to this research being well aligned with the National Institute of Nursing Research's focus on integrating biology and behavior, and its potential for elucidating modifiable factors involved the CE pathway, this project also allows for the candidate to gain training in order to develop into an independent researcher. Methods: Having a background studying the catechol estrogen pathway from an epidemiologic perspective, Dr. Reding proposes to gain training in behavioral and nursing research in order to implement an intervention employing a cognitive behavioral therapy (CBT) approach based in a clinical setting. The lifestyle intervention will focus on motivating patients from primary care clinics who are at a high risk for breast and/or endometrial cancer and leading a sedentary lifestyle to initiate changes to improve their diet and increase their physical activity. In addition to formal training during the mentored phase, the applicant will gain research experiences within existing studies of CBT interventions, as well as conduct a pilot study using 125 women from a well-characterized, existing study population in order to characterize the novel biomarkers, namely hydroxy estrogen bound-adducts (HEBA) and their unbound counterparts (Specific Aim 1). During the independent phase, the candidate will implement a feasibility study in order to identify the practicability of implementing a lifestyle intervention within the target population (Specific Aims 2), determine the variability of the biomarker in this population (Specific Aim 3) and explore the impact of the intervention on body composition (Specific Aim 4). Results: The results from the pilot and feasibility studies will be used to provide preliminary data for an R01 application proposing to investigate the hypothesis that a diet and exercise intervention can impact the balance of metabolites in the CE pathway with a particular focus on novel biomarkers. Conclusion: The K99 award mechanism will foster Dr. Reding's career growth by enabling the candidate to develop expertise in a new direction of research, namely in the implementation of behaviorally based clinical interventions, in order to reach her long-term career goals of attaining a faculty position where she would be able to launch an independent line of research investigating the impact of lifestyle interventions on biological mechanisms.